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>Mice lacking the Yap and Taz genes that control liver size have larger livers…but they also have liver cancers, and worse regeneration from liver injury.16 Similarly, mutant mice lacking Hippo signaling have unusually large livers that don’t stop growing when they hit the usual “maximal size”…but they also get lots of liver tumors not seen in wild-type mice.17
Notably, Yap and Taz are downstream mediators of Hippo signaling so these studies are looking at the same thing.
I guess the missile knows where it is
Well, actually the missile knows where it isn't.
Turns out that several of the main studies about cerebrolysin may have been fraudulent: https://www.science.org/content/article/research-misconduct-finding-neuroscientist-eliezer-masliah-papers-under-suspicion
A lot of "weird testis genes" are epigenetically silenced in somatic cells (for example, suppressed by DNA methylation), and this epigenetic control becomes defective in disease states, especially cancer. There are a whole category of "cancer/testis antigens," proteins which are usually expressed only in the testis but which are expressed in cancers like melanoma. There are currently cancer vaccine trials to target immune responses against these proteins (which might also cause male infertility but that's probably an acceptable tradeoff).
Maybe something similar is going on with LINC01609 in Alzheimer's.
Dietary vitamin A (beta carotene) is not the active form of vitamin A (retinoic acid), it needs to be converted into the active form by the body's enzymes. Once retinoic acid is formed, it can bind to the retinoic acid receptor and regulate gene expression.
Retinoid treatment bypasses these enzymes and directly activates retinoic acid receptor signaling. So, eating vitamin A in the form of beta carotene won't directly increase retinoic acid receptor signaling because the rate-limiting step is the enzymes, but retinoid treatment will. This is also why you can't overdose on vitamin A by eating carrots.
Does this meet your criteria for a good answer? If not I can explain in more detail.
Lastly, you shouldn’t use Retinoids if you’re pregnant or likely to become pregnant.
This needs more emphasis. Retinoid signaling is very important for embryonic development, so excess retinoids will really mess up your baby.
I agree with this. There's a lot of snake oil out there and cerebrolysin is just one example. I had no idea it was so popular though.
200 mg/day is a pretty high dose (at least for me)
Not just mammals, as far as I know it only works in E. coli bacteria and not in any eukaryotes.
Source:
https://www.nature.com/articles/s41586-024-07552-4
Interestingly there was just a similar article in the news section of Science, about glacier geoengineering.
https://www.science.org/content/article/avoid-sea-level-rise-some-researchers-want-build-barriers-around-world-s-most
>I'm using Quaise Energy as an example of a much larger overall trend - of the inability of investors to effectively evaluate technologies. The ability of investors to recognize good technical evaluations is the key thing that's lacking in the economy today; there are plenty of good ideas and there's plenty of investment capital.
Yeah, just look at Varda "manufacture drugs in space," and Colossal "bring back the wooly mammoth." It just doesn't make sense for these to be profitable businesses.
Reposting a comment from the Substack:
>Recently, he solved this problem!
I'm flattered, but I actually haven't gotten all the way to haploid cells yet. As I wrote in my preprint and associated blog post, right now I can get the cells to initiate meiosis and progress about 3/4 of the way through it (specifically, to the pachytene stage). I'm still working on getting all the way to haploid cells and I have a few potentially promising approaches for this.
Very cool. I wonder which University of Missouri lab the lentiviral plasmid leaked from...
I went a few times but eventually got grossed out by all the mold. (At least they don't sell live pangolins there.)
At the time, one of the biggest problems in physics was the “Blackbody spectrum”, which describes the spectrum of electromagnetic wavelengths emitted by a Blackbody. The problem with it was that the emitted spectrum was not explainable by known physics. Einstein achieved a breakthrough by considering light not just as a wave, but also as light quanta. Although this idea sufficiently explained the Blackbody spectrum, physicists (at least almost) unanimously rejected it. The fight between the “light is corpuscles” and “light is a wave” faction had been decided a century ago, with a clear victory for the “wave” faction.
I thought blackbody radiation was Planck, not Einstein.
Interestingly, many cancer "neoantigens" (for example, MAGEB1) are also expressed in meiotic cells in the testis. This is because they're usually epigenetically suppressed in healthy tissues, but cancer cells have messed up epigenomes. See: https://en.wikipedia.org/wiki/Cancer/testis_antigens
Also, I would disagree that synthesizing long polypeptides is easier than synthesizing long mRNAs. With polypeptides you have 20 amino acids to work with, and some require special treatment (protecting groups on sidechains). With mRNAs the chemistry is much simpler.
Testosterone will land you in more legal trouble than modafinil.
Compounding pharmacies are gray-market. (Buying on "evolutionpeptides.com" would be black-market.)
No mention of modafinil? It's quite useful for maintaining productivity on low amounts of sleep.
Semaglutide is the real-deal weight loss drug we have been praying for. It works well for 70%+ of people. Losing and keeping weight off is so difficult that prior to ozempic, it was reasonable advice to preach acceptance or extremely restricted diets. Prior to Semaglutide, I used to assume that most of my friends who wanted to lose weight would fail. Now I assume they will trivially succeed if they get on the drugs. Here is how to get on Semaglutide:
- I purchased sema, for myself and others, on this site: https://evolutionpeptides.com/products/semaglutide-10mg?variant=42834747326660. It has been a reliable supplier for me. Reliability can always change, but for now, it's where I would go.
- Start with a dose of 0.25mg. Increase your dose approximately every four weeks. Stay on lower dosages as long as possible. Tolerance can increase rapidly. For example, the official guidelines say to double your dose after each of the first two months of treatment. I would try to increase dosages more slowly.
- Gray market semaglutide is sold as a powder. You need to mix it into a solution to inject. Search for reconstitution solution.
- You also need needles. Any insulin needle will work fine but some hurt less than others. Here are the ones I use.
- To make the solution, I draw 100 units of reconstitution (a 'full' vial) solution into the needle. I then squirt the solution into the sema vial and repeat this process again. This means 5mg of semaglutide per 200 units of solution. So, to do a 0.25 starting dose, I would inject 10 units of mixed sema solution into my deltoid. It doesn't really matter if you inject into fat or muscle.
Semaglutide feels weird in many ways and makes many people nauseous. Fake Dr. Sapphire's medical advice is to use gray market odansetron to manage nausea. But dramamine is OTC in the USA and most other countries and also works well. Don't expect insanely rapid weight loss. It's normal to lose 1-2 pounds a week, which is honestly quite quick!
Injecting anything from the "gray-market" is quite risky, since it may not be sterile. People have died from such things (for example: https://en.wikipedia.org/wiki/New_England_Compounding_Center_meningitis_outbreak)
For biology, JoVE ("Journal of Visual Experiments") is a very good source of videos like this. https://www.jove.com/ Unfortunately it's paywalled.
I agree, I think the most likely version of the lab leak scenario does not involve an engineered virus. Personally I would say 60% chance zoonotic, 40% chance lab leak.
A commenter on my Substack got much better results using Claude 3 Opus.
Spearman (rank) correlation is often a good alternative for nonlinear relationships.
>heats the water (adenosine diphosphate, ADP) to a closely related, higher-energy form (adenosine triphosphate, ATP), which is steam.
I would say protons are the steam, not the ATP/ADP. The electron transport chain "pressurizes" protons by pumping them, and then the protons flow through the ATP synthase "turbine".
I think the exact origin of SARS-CoV-2 is a largely irrelevant question.
Given that it's plausible it could have come either from a wet market or risky biological research, we should shut down both.
(Personally I would say 60% "wet market", 40% "unintentional lab leak")
That make sense. If I were going for sarcasm I would have said Kary Mullis.
A Nobel-winning scientist like Gregg Semenza would obviously be the best possible expert
Funny you should say that . . .
https://retractionwatch.com/2023/10/02/nobel-prize-winner-gregg-semenza-tallies-tenth-retraction/
https://www.nature.com/articles/d41586-022-03032-9
Emmett Shear on college-level organic chemistry. His experience was that the class was composed of a mix of science track and premed track students. The science students are there to actually learn and retain the material, so even though it’s a massive amount of compounding facts you have to learn, they do fine. Whereas the premed students are happy to do the work, but are thinking of the class as a structural barrier rather than source of information, so they cram rather than retaining information, and then struggle. So it is a question of motivation. How do we get students, across the board, to be motivated by actually caring about the material?
As a former TA for organic chemistry, I can definitely confirm this.
As a scientist I strongly agree. It seems like there's been a few steps towards this in recent years, for example with things like the Arc Institute or FROs. Hopefully this model gets the attention of government funders.
>I haven’t heard a “Polack joke” in years and I wouldn’t be surprised if the rising generation is mostly unaware that there ever was such a thing.
On the contrary, I heard one at an ACX meetup in Boston in summer 2023. I was not amused.
>I think it makes sense for some country with a high rate of alcohol flush reaction to legalize using 1-butanol or oxane as a substitute for ethanol in drinks served at bars and restaurants.
The only downside is that butanol tastes pretty awful.
I think it would be useful to examine cases where important patents for Input X expired and prices came down quickly, allowing Input X to be used to produce much more of Product Y.
That is very wrong. Diamond is hard to make with enzymes because they can't stabilize intermediates for adding carbons to diamond.
As a biochemist, I agree.
It does integrate into the genome. It's gene therapy, but not gene editing (which means editing an existing gene).
Consolidating my previous comments:
I discussed this project with GeneSmith and I think it is promising, though very challenging to implement in practice. The hardest part will be safely and efficiently delivering the editing agent to a large fraction of the cells in the brain.
Some other points:
CAR T-cell therapy, a treatment for certain types of cancer, requires the removal of white blood cells via IV, genetic modification of those cells outside the body, culturing of the modified cells, chemotherapy to kill off most of the remaining unmodified cells in the body, and reinjection of the genetically engineered ones. The price is $500,000 to $1,000,000.
And it only modifies a single gene.
This makes it sound like CAR-T is gene editing, but it isn't. Instead of editing a gene, it introduces a new one (a chimeric T-cell receptor). Although some companies are working on gene editing to enhance CAR-Ts.
I also know of a PHD student in George Church’s lab that was able to make several thousand edits in the same cell at the same time by targeting a gene that has several thousand copies spread throughout the genome.
The paper reporting this was here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229841/
CAR T-cell therapy, a treatment for certain types of cancer, requires the removal of white blood cells via IV, genetic modification of those cells outside the body, culturing of the modified cells, chemotherapy to kill off most of the remaining unmodified cells in the body, and reinjection of the genetically engineered ones. The price is $500,000 to $1,000,000.
And it only modifies a single gene.
This makes it sound like CAR-T is gene editing, but it isn't. Instead of editing a gene, it introduces a new one (a chimeric T-cell receptor). Although some companies are working on gene editing to enhance CAR-Ts.
There's also a lot of statistics that go into designing experiments (rather than analyzing them afterwards). For example, fractional factorial designs, or adaptive clinical trials
Yeah, Yudkowsky doesn't know what he's talking about here.
Still, one of the ways protein engineers can make proteins more heat-stable is by adding more covalent bonds (in particular, disulfide crosslinks to prevent unfolding). See the many results for https://scholar.google.com/scholar?q=thermostability+disulfide+bond&hl=en
Overhead. Researchers typically spend 30–50% of their time on grants
To me, "overhead" means "I only get to spend 58% of the money I raise, Harvard takes the other 42%".
>And even without LLMs, the number of graduate students who would be capable of doing this has been increasing quickly as technological progress and biological infrastructure decrease the difficulty.
Grad student mental health support might be the next big EA cause area.
To be fair, the amyloid hypothesis seemed promising 20 years ago, and was well worth investigating. It's just that researchers should have investigated alternative hypotheses too.
Still I agree with the other examples.
Which means getting government grants, from which the university takes a cut of overhead.
I know quite a few researchers working on bioengineered organs, and the fact that some people donate their kidneys does not make those researchers work less hard.
>Much higher than the anthrax attacks you mention. People in biosecurity think that the tails are more like billions dead or the end of civilization. (I'm not sure if I believe them, the public object level cases for this don't seem that amazing due to info-hazard concerns.)
As a biologist who has thought about these kinds of things (and participated in a forecasting group about them), I agree. (And there are very good reasons for not making the object-level cases public!)
>You can check this out very easily in seconds and verify that you could do the same thing with less effort than you've probably put into some video games.
Indeed. Donating sperm over the Internet costs approximately $125 per donation (most of which is Fedex overnight shipping costs, and often the recipient will cover these) and has about a 10% pregnancy success rate per cycle.
See: https://www.irvinesci.com/refrigeration-medium-tyb-with-gentamicin.html
and https://www.justababy.com/
See also: Reagan and "The Day After"
I agree with the other commenters here: access to Google and NCBI/PubMed should be taken as a control group.
"Paired-end reads" is the most common way to phrase it (at least in my experience). One paired-end read comprises both ends and is equivalent to a read pair. I agree that "read pair" may be less confusing.